This is an integrated program project to investigate the mechanisms by which bacterial cell walls which are resistant to biodegradation produce chronic inflammatory disorders. Our emphasis will be on an experimental model of rheumatoid arthritis in rats. The initial studies will involve group A, group B, and group D streptococci, but other selected bacteria will be investigated. We will study the way in which the bacterial cell is degraded in vivo; persistence and toxic properties of digestion products; and the immunological, genetic and environmental factors which control processing, transport, localization and persistence of these foreign materials in tissue. Pathways of tissue injury to be investigated include: direct toxicity of peptidoglycan-polysaccharide complexes of cell wall, activation of complement by peptidoglycan, activation of macrophages to become effector cells, cell mediated immunity and immune complexes of antibody and persistent cell wall antigens. Lysosomal enzymes which participate in elimination of bacteria or contribute to tissue injury will be identified in rat and human phagocytic cells. The relationship of this experimental model to human disease will be pursued by comparative histological, ultramicroscopic, radiological and immunochemical assessment of evolving human and animal lesions. Detailed study of this animal model will provide insight into problems of etiological factors, mechanisms of articular erosion and mechanisms of remission in rheumatoid arthritis in man.